Computational and Structural Investigation of Deleterious Functional SNPs in Breast Cancer BRCA2 Gene

Rajasekaran, R.; Doss, George Priya; Sudandiradoss, C.; Ramanathan, K.; Purohit, Rituraj; Sethumadhavan, Rao

doi:10.1016/s1872-2075(08)60042-4

Cited by 41 publications

(30 citation statements)

References 26 publications

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“…Although some authors (Kwiatkowska et al, 2001;Stegel et al, 2011) consider BRCA2 nonsense mutation c.9371A > T (Asn3124Ile) as an UV, our in silico analysis agreed with its previously predicted (Karchin et al, 2008;Rajasekaran et al, 2008). Since the Asn3124Ile substitution is located at highly conserved protein position in the OB3 domain, one of the oligonucleotide ssDNA-binding fold motifs, the aminoacid change from hydrophilic and negatively charged asparagine to hydrophobic isoleucine should be interpreted as a missense mutation affecting the BRCA2 role in the repair of double-strand DNA breaks by homologous recombination (Holloman, 2011;Yang et al, 2002).…”

Section: Novel Mutations In Brca1 and Brca2 Genessupporting

confidence: 88%

Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia

Levanat

Musani

Cvok³

et al. 2012

Gene

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Section: Novel Mutations In Brca1 and Brca2 Genessupporting

confidence: 88%

Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia

Levanat

Musani

Cvok³

et al. 2012

Gene

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“…A constitutional confirmed pathogenic missense mutation in BRCA2 c.9371A>T (p.Asn3124Ile) was detected in sample 608H (Table ) [Karchin et al., ; Rajasekaran et al., ; Surowy et al., ]. This mutation affects an evolutionary conserved nucleotide, and solely the reference allele is present in the 1000 Genomes and ESP cohorts (Table ; Supp.…”

Section: Resultsmentioning

confidence: 99%

Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

et al. 2015

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Somatic mosaicism for DNA copy-number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array-based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC-CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.

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“…The BRCA2 gene functions as a tumoursuppressor gene and plays a pivotal role in the control of the HR repair pathway (Venkitaraman 2002). BRCA2 rs1799943 SNP might modulate BRCA2 transcript levels as indicated by in silico analysis (Rajasekaran et al 2008). The BRCA2 rs15869 SNP is located in the 3 0 -UTR, which might affect mRNA stability and translation.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in double-strand breaks repair genes are associated with impaired fertility in Chinese population

Ji¹,

Yan²,

Liu³

et al. 2013

Reproduction

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The DNA double-strand breaks (DSBs) repair pathway plays a critical role in repairing double-strand breaks, and genetic variants in DSBs repair pathway genes are potential risk factors for various diseases. To test the hypothesis that polymorphisms in DSBs genes are associated with susceptibility to male infertility, we examined 11 single nucleotide polymorphisms in eight key DSBs genes (XRCC3, XRCC2, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in 580 infertility cases and 580 controls from a Chinese population-based case-control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform, and sperm DNA fragmentation was detected using the TUNEL assay. The adjusted odds ratio (OR) and 95% CI were estimated using logistic regression. The results indicate that LIG4 rs1805388 (Ex2C54COT, Thr9Ile) T allele could increase the susceptibility to male infertility (adjusted ORZ2.78; 95% CI, 1.77-4.36 for TT genotype; and adjusted ORZ1.58; 95% CI, 1.77-4.36 for TC genotype respectively). In addition, the homozygous variant genotype GG of RAG1 rs2227973 (AOG, K820R) was associated with a significantly increased risk of male infertility (adjusted OR, 1.44; 95% CI, 1.01-2.04). Moreover, linear regression analysis revealed that carriers of LIG4 rs1805388 or RAG1 rs2227973 variants had a significantly higher level of sperm DNA fragmentation and that T allele carriers of LIG4 rs1805388 also had a lower level of sperm concentration when compared with common homozygous genotype carriers. This study demonstrates, for the first time, to our knowledge, that functional variants of RAG1 rs2227973 and LIG4 rs1805388 are associated with susceptibility to male infertility.

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Computational and Structural Investigation of Deleterious Functional SNPs in Breast Cancer BRCA2 Gene

Cited by 41 publications

References 26 publications

Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia

Three novel BRCA1/BRCA2 mutations in breast/ovarian cancer families in Croatia

Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Polymorphisms in double-strand breaks repair genes are associated with impaired fertility in Chinese population

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